Gastric cancer is one of the major cancers that cause death. Gastric cancer is histopathologically classified into differentiated gastric cancer and undifferentiated gastric cancer, where the latter includes poorly differentiated adenocarcinoma, signet-ring cell carcinoma, mucinous carcinoma and the like.
In the case of undifferentiated gastric cancer, cancer cells are likely to diffuse and also likely to develop fibrosis that leads to scirrhous gastric cancer. Undifferentiated gastric cancer is commonly observed in young people, and is known to cause invasive proliferation and metastasis, indicating a poor prognosis (Clinical Cancer Research. 2(8), 1373-1381, 1996).
FGFR2 (also referred to as “K-sam”) is amplified in diffuse-type gastric cancer, namely, undifferentiated gastric cancer and is known to be involved in malignant alteration of cancer (Clinical Cancer Research. 2(8), 1373-1381, 1996, Journal of Cancer Research and Clinical Oncology. 127, 207-216, 2001). FGFR2 gene is reported to be amplified in 33% of patients with undifferentiated gastric cancer (Journal of Cancer Research and Clinical Oncology. 127, 207-216, 2001), and FGFR2 is reported to be positive in about 50% of patients with undifferentiated gastric cancer (Clinical Cancer Research. 2(8), 1373-1381, 1996).
FGFR2 gene induces transformation of NIH3T3 cell, and the transformed cell is reported to show tumorigenicity in nude mice (Cancer Research. 54, 3237-3241, 1994). Furthermore, FGFR2 truncated at C-terminal is reported to have strong transformation activity and predominantly expressed in undifferentiated gastric cancer cell line (Clinical Cancer Research. 2(8), 1373-1381, 1996, Cancer Research. 54, 3237-3241, 1994). For example, FGFR2 having residues downstream from tyrosine at 769 deleted is reported to have high transformation activity (Cancer Research. 54, 3237-3241, 1994).
It is also reported that FGFR2 gene is amplified in poorly differentiated gastric cancer, particularly scirrhous gastric cancer, while FGFR2 protein having C-terminal (including tyrosine residues 780, 784 and 813) deleted is specifically expressed in scirrhous gastric cancer (Cancer Research. 59(24), 6080-6086, 1999). Amplification of activated FGFR2 is reported to cause tumor growth in scirrhous gastric cancer (Cancer Research. 59(24), 6080-6086, 1999).
A FGFR2 inhibitory substance, diphenylamine derivative, is reported to dose-dependently suppress cell growth of a human scirrhous gastric cell line and show anti-tumor effect on a subcutaneous xenograft model of human scirrhous gastric cell line (Bioorganic and Medicinal Chemistry Letters. 14(4), 875-879, 2004).
A FGFR2 inhibitory substance, 4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]quinazoline, is suggested to be effective on gastric cancer overexpressing K-sam (Proceeding of the American Association for Cancer Research. 47, 890, 2006).
Accordingly, a FGFR2 inhibitory substance is suggested to show antiproliferative action and anti-tumor effect on undifferentiated gastric cancer, preferably poorly differentiated adenocarcinoma, signet-ring cell carcinoma, mucinous carcinoma and scirrhous gastric cancer.
Here, a compound represented by General Formula (I) is known as an antiangiogenic substance (International Publication No. 02/32872, International Publication No. 2004/080462 and International Publication No. 2005/063713). However, there is no report about the compound represented by General formula (I) having FGFR2 inhibitory activity.